1. Field of the Invention
The present invention relates to a method and reagent for the opening of the cyclopropyl ring of vinyl cyclopropyl compounds with the simultaneous introduction of a nucleophile into the product compound. More particularly, the present invention relates to a method of converting unsaturated fatty acids containing a vinyl cyclopropyl structure to a hydroxy or hydroperoxy fatty acid.
2. Description of the Prior Art
Both the hydroxy and hydroperoxy derivatives of certain fatty acids conventionally formed by the action of lipoxygenase enzymes on various acid substrates are of medical interest because it is believed that they play significant roles in platelet pharmacology and in the inflammation of various tissues. For example, 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid exhibits chemotatic activity on neutrophils. The corresponding hydroperoxy derivative as well as other hydroperoxy positional isomers modulate the enzymes that control prostaglandin metabolism. E. J. Corey et al, J. Am. Chem. Soc., 100, 1942 (1978) recently have described a total synthesis of this compound.
Recently, two previously unknown monohydroxy C.sub.20 fatty acids, 5-L-hydroxy-6,8,11,14-eicosatetraenoic acid, whose chemical and enzymatic synthesis has recently been reported by E. J. Corey et al J. Am. Chem. Soc., 102, 1435 (1980), and 8-L-hydroxy-9,11,14-eicosatetraenoic acid, have been isolated from rabbit neutrophils. The structure of these compounds which contains a cis, trans conjugated diene unit suggests that the mono-hydroxy acid compounds are probably formed from the corresponding intermediate hydroperoxy compounds. In fact, it has been demonstrated that the hydroxy group of 5-L-hydroxy-6,8,11,14-eicosatetraenoic acid is derived from molecular oxygen which is a finding consistent with the intermediacy of the corresponding hydroperoxy compound.
Interest in all of the above-discussed compounds as well as their hydroperoxy intermediates has also been heightened by the postulate that 5-L-hydroperoxy-6,8,11,14-eicosatetraenoic acid is a key intermediate in the biosynthesis of leukotrienes. One member of this important group of compounds is leukotriene C, which is the slow reacting substance of anaphylaxis, which causes prolonged smooth muscle contraction that is not inhibited by conventional anti-histamines. Leukotriene C is also believed to be intimately involved in the allergic response and may very well be an important factor in certain types of asthma. Samuelsson et al (Proc. Nat. Acad. Sci, 76, 4275 (1979)) has suggested that leukotriene C is biochemically prepared by a series of reactions in which 5-L-hydroperoxy-6,8,11,14- eicosatetraenoic acid (an arachidonic acid hydroperoxide) is converted to leukotriene A, which is an epoxide. Leukotriene A is then converted to leukotriene C by reaction with the cysteine sulfur nucleophile. Even though the above suggested synthetic scheme has not been unequivocally established, nevertheless the fundamentally important function which the arachidonic acid hydroperoxide derivatives exhibit in inflammation and in certain forms of asthma is gaining increased recognition by the scientific community.
In view of the above developments there is an obvious need for a study of the oxidative metabolism of unsaturated fatty acid compounds. The oxidation products (endoperoxides and hydroperoxides) are evidently important factors in such major traumatic events as the inflammation process, blood platelet aggregation and consequently heart attack and stroke and the allergic response. Studies, therefore, directed to an understanding of the fundamental chemistry involved in fatty acid oxidation are believed to be important to a proper understanding of these pathological conditions. Previous attempts at synthesizing various hydroxy and hydroperoxy derivatives of various unsaturated compounds have been limited to enzyme catalyzed oxidation reactions of unsaturated fatty acids and such non-enzymatic reactions as the reaction of singlet oxygen generated by photolysis of molecular oxygen with the likes of arachidonic acid. (Porter et al, J. Org. Chem., 44, 3177 (1979)). Another proposed method of synthesis involves the autooxidation of arachidonic acid. However, in both known non-enzymatic oxidation reactions, a complex mixture of product compounds is obtained in low yield which requires tedious chromatographic separation. A need, therefore, continues to exist for a method by which unsaturated fatty acid substrates can be oxidized to just a few, rather than a broad spectrum of possible corresponding hydroperoxy and hydroxy derivatives in good yield.